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Anticoagulation in Atrial Fibrillation:To Bridge or Not to Bridge?
Katie Galbreath, PharmD
Sanford Medical Center Fargo
October 13, 2015
Introduction
• MW is a 63 year old male s/p right kidney biopsy receiving OAC therapy
with warfarin for atrial fibrillation. Warfarin was held 5 days prior to
procedure. PMH is significant for type 2 diabetes mellitus, coronary artery
disease, and hypertension. No previous stroke or TIA. INR upon arrival
back to the medical unit is 1.1.
• The MD orders enoxaparin 1mg/kg BID to start tomorrow AM, and warfarin
to re-start this evening. What do you do?
– Verify the enoxaparin order of 1mg/kg BID
– Call the MD to suggest bridging with UFH instead of enoxaparin.
– Call the MD to suggest not bridging in this patient
– Call the MD to suggest prophylaxis enoxaparin dosing (40mg daily)
Objectives
1. Summarize current guidelines regarding
anticoagulation and bridging anticoagulation in
atrial fibrillation (AF)
2. Identify risks and benefits of bridging
anticoagulation
3. Use recent literature data to guide bridging
anticoagulation decision making
Abbreviations
• DVT: deep vein thrombosis
• INR: international normalized ratio
• LOE: level of evidence
• LMWH: low molecular weight heparin
• MHV: mechanical heart valve
• MI: myocardial infarction
• NOAC: novel oral anticoagulants
• NVAF: non-valvular atrial fibrillation
• OAC: oral anticoagulation
• PE: pulmonary embolism
• UFH: unfractionated heparin
• SC: subcutaneous
• TIA: transient ischemic attack
• VKA: vitamin K antagonist
What is Atrial Fibrillation?
Hypertension
Hyperthyroidism
Congestive Heart
Failure
Valvular Disease
Sleep apnea
Most common rhythm
disturbance
Lifetime prevalence: 16%
Yearly incidence of new AF:
1.6%
Independent risk factor for stroke
and thromboembolism
5-fold increased risk of stroke
Lip et al. Lancet. 2012.
Electrolyte imbalances
Surgery
Stroke Risk• In patients with NVAF, the CHA2DS2-VASc score is recommended for assessment of
stroke risk (Class I, LOE B)
January et al. J Am Coll Cardiol. 2014.
CHADS2 Score
Clinical Characteristic Points
CHF 1
Hypertension 1
Age ≥ 75 1
Diabetes Mellitus 1
Stoke/TIA 2
January et al. J Am Coll Cardiol. 2014.
• In patients with NVAF, the CHA2DS2-VASc score is recommended for assessment of
stroke risk (Class I, LOE B)
CHA2DS2-VASC Score
Clinical Characteristic Points
CHF 1
Hypertension 1
Age ≥ 75 1
Diabetes Mellitus 1
Stoke/TIA 2
Vascular disease 1
Age (65-74) 1
Sex category
(female)
1
Stroke Risk
Stroke Risk• In patients with NVAF, the CHA2DS2-VASc score is recommended for assessment of
stroke risk (Class I, LOE B)
Adjusted Stroke Rate (% per year)
CHADS2 Score CHADS2 (%)
0 1.9
1 2.8
2 4.0
3 5.9
4 8.5
5 12.5
6 18.2
January et al. J Am Coll Cardiol. 2014.
Stroke Risk• In patients with NVAF, the CHA2DS2-VASc score is recommended for assessment of
stroke risk (Class I, LOE B)
Adjusted Stroke Rate (% per year)
CHA2DS2-VASc
Score
CHA2DS2-VASc
(%)
0 0
1 1.3
2 2.2
3 3.2
4 4.0
5 6.7
6 9.8
7 9.6
8 6.7
9 15.2January et al. J Am Coll Cardiol. 2014.
Stroke Risk• In patients with NVAF, the CHA2DS2-VASc score is recommended for assessment of
stroke risk (Class I, LOE B)
Adjusted Stroke Rate (% per year)
CHADS2 Score CHADS2
(%)
CHA2DS2-VASc
Score
CHA2DS2-VASc
(%)
0 1.9 0 0
1 2.8 1 1.3
2 4.0 2 2.2
3 5.9 3 3.2
4 8.5 4 4.0
5 12.5 5 6.7
6 18.2 6 9.8
7 9.6
8 6.7
9 15.2January et al. J Am Coll Cardiol. 2014.
Guidelines for OAC in AF
• NVAF with prior stroke, TIA, or
a CHA2DS2-VASc ≥ 2
– OAC is recommended
• Warfarin
– INR 2.0 to 3.0
– Class I, LOE A
• Dabigatran (Pradaxa®)
– Class I, LOE B
• Rivaroxaban (Xarelto®)
– Class I, LOE B
• Apixaban (Eliquis®)
– Class I, LOE B
• NVAF and a CHA2DSs-VASc of 1
– No antithrombotic therapy, or
treatment with OAC or ASA may
be considered
• Class IIb, LOE C
• NVAF and a CHA2DS2-VASc of 0
– Reasonable to omit
antithrombotic therapy
• Class IIa, LOE B
January et al. J Am Coll Cardiol. 2014.
Bridging
• Bridging anticoagulation:
– Giving a short-acting anticoagulant, consisting of SC
LMWH or UFH for ~10 to 12 day period during
interruption of VKA therapy when the INR is not within
therapeutic range
– Minimize risk of thromboembolism
Douketis et al. Chest. 2012.
Bridging Considerations
• Mechanical valve status
• Assessment of thromboembolic risk (CHADS2 score)
• Type of procedure
• Bleeding risk of the patient
• Risk vs. benefit
Bridging
• AF with MHV who require interruption of warfarin
or new anticoagulants for procedures
– Bridging therapy with UFH or LMWH is recommended
– Decisions on bridging therapy should balance the
risks of stroke and bleeding
– Class I, LOE C
January et al. J Am Coll Cardiol. 2014.
Bridging
• AF without MHV who require interruption of
warfarin or new anticoagulants for procedures
– Bridging therapy should balance the risks of stroke
and bleeding and the duration of time a patient will
not be anticoagulated
– Class I, LOE C
January et al. J Am Coll Cardiol. 2014.
Thromboembolism Risk Stratification
• Low risk
– CHADS2 score 0 to 2 (no prior stroke or TIA)
– No bridging instead of bridging anticoagulation
• Class II, LOE C
• Moderate risk
– CHADS2 score 3 or 4
– Bridging or no bridging based on assessment of individual patient and surgery related
factors
• High Risk
– CHADS2 score of 5 or 6, recent stroke or TIA, rheumatic valvular heart disease
– Bridging anticoagulation instead of no bridging anticoagulation
• Class II, LOE C
Douketis et al. Chest. 2012.
Procedural Bleeding Risk
High Risk Bleeding Procedures
• All cardiac and neurosurgeries
• Kidney/Liver biopsy
• Chest tube placement
• Joint replacement
• Hysterectomy
• Hickman and tunneled dialysis
catheter placement
Low Risk Bleeding Procedures
• Endoscopy (+/- mucosal biopsy)
• Cataract surgery
• Bone marrow biopsy
• Dental extractions
• Dermatologic surgery
• Joint aspiration
Baron et al. N Engl J Med. 2013.
Bleeding Risk
HAS-BLED
Clinical Characteristic Points
Hypertension 1
Abnormal renal/liver function 1 or 2
Stroke 1
Bleeding history/predisposition 1
Labile INR’s (for patients on warfarin) 1
Elderly (>65 years of age) 1
Drugs (concomitant aspirin or NSAIDS) or alcohol
abuse
1 or 2
Max: 9 points
Lane & Lip. Circulation. 2012.
Bridging
Bleeding RiskThromboemboli
c risk
• Use of any bridging
anticoagulant is “off label”
Douketis et al. Chest. 2014.
Bridging: What Do We Know?
• Few, randomized controlled trials to guide decision making
– LOE C: Recommendation that procedure/treatment is useful/effective
• Weak recommendation
• Only expert opinion, case studies, or standard of care
• Guidelines suggest utilizing patient and surgery specific
information to guide decision making
• Benefit of bridging anticoagulation should outweigh risk of
bleeding
Bridging: What Do We Know?
• Siegal et al 2012:
– Meta-analysis evaluating safety and efficacy of periprocedural bridging
anticoagulation
– 34 studies included
– Largest systematic review and meta analysis of the efficacy and safety
of periprocedural bridging anticoagulation
• 44% of bridged patients had AF
Siegel et al. Circulation. 2012.
Bridging: What Do We Know?
Group Thromboembolic
events, %
Major bleeding,
%
Overall bleeding,
%
Bridged 0.9 4.2 13.1
Not bridged 0.6 0.9 3.4
Siegel et al. Circulation. 2012.
Use and Outcomes Associated with Bridging During
Anticoagulation Interruptions in Patient’s with Atrial
Fibrillation: Findings from the Outcomes Registry for Better
Informed Treatment of Atrial Fibrillation (ORBIT-AF).
Steinberg BA, Peterson ED, Kim S, et al. Circulation. 2014.
ORBIT-AF
• Study Question:
– What are the outcomes among patients with AF
requiring temporary interruption of OAC who received
bridging anticoagulation versus those who did not
receive bridging anticoagulation?
ORBIT-AF
• Methods
– The Outcomes Registry for Better Informed Treatment
of Atrial Fibrillation (ORBIT-AF)
• National, community-based registry of outpatients with AF
– Prospective, observational
Steinberg et al. Circulation. 2014.
ORBIT-AF
• Methods
– Data collection from patient medical records
• Baseline and every 6 months
– Type of procedure and bridging anticoagulation used
– Interruptions recorded for procedures only
Steinberg et al. Circulation. 2014.
ORBIT-AF
Inclusion • Age >18 years
• Documented AF
Exclusion • <1 follow up visit
• Not on baseline OAC
• Interruptions not relating to surgery
or procedure
Steinberg et al. Circulation. 2014.
ORBIT-AF
• Outcomes*
– Myocardial infarction
– Stroke or systemic embolism
– Major bleeding
– Cause-specific hospitalization
– Death
*Within 30 days following procedure for interruption Steinberg et al. Circulation. 2014.
ORBIT-AF
• Interruptions:
– Cardiac catheterization
– Catheter ablation
– Endoscopy (GI, bronchoscopic, genitourinary)
– Cardiac surgery
– Non-cardiac surgery (not further specified)
– Device implantation
– Dental procedures
– Other (not further specified)
Steinberg et al. Circulation. 2014.
0
10
20
30
40
50
% of Temporary Interruptions with Bridging
Adapted from: Steinberg et al. Circulation. 2014.
10,132 Patients identified
9,642Patients included
490Excluded
(<1 follow up visit)
2,270Excluded
(not on baseline OAC)
Methods
7,372FINAL COHORT
Steinberg et al. Circulation. 2014.
2,803 Reported
interruptions
2,138No bridging
therapy
665Bridging therapy
487LMWH (74%)
97UFH (15%)
7Fondaparinux
(1%)
76Other (11%)
Methods7,372
FINAL COHORT
Steinberg et al. Circulation. 2014.
ORBIT-AF
• Bridging anticoagulation in ORBIT-AF:
– Anticoagulant temporarily administered in
place of chronic therapy, for the purpose of
stroke prevention before, during, or after the
periprocedural period
Steinberg et al. Circulation. 2014.
2,803 Reported
interruptions
2,138No bridging
therapy
665Bridging therapy
487LMWH (74%)
97UFH (15%)
7Fondaparinux
(1%)
76Other (11%)
Methods7,372
FINAL COHORT
Steinberg et al. Circulation. 2014.
Baseline demographics, past medical history, and laboratory studies by incidence of temporary
interruption
≥1 temporary interruption (n = 2200)
No temporary
interruption
(5172)
No bridging
(N=1608)
Bridging
(N=592)
P value
(no bridging
vs. bridging)
Age 76 (68-82) 75 (68-81) 74 (67-80) 0.009
CHADS2 scores, mean (SD) 2.4 (1.3) 2.34 (1.21) 2.53 (1.31) 0.004
CHA2DS2VASc score, mean (SD) 4.0 (1.7) 4.03 (1.62) 4.25 (1.74) 0.01
ORBIT-AF
Adapted from: Steinberg et al. Circulation. 2014.
Baseline demographics, past medical history, and laboratory studies by incidence of temporary
interruption
≥1 temporary interruption (n = 2200)
No temporary
interruption
(5172)
No bridging
(N=1608)
Bridging
(N=592)
P value
(no bridging vs.
bridging)
Significant valve disease
• Moderate/severe mitral
stenosis
• Prior mechanical valve
replacement
27
1.7
3.6
37
1.1
2.4
34
2.5
9.6
0.0006
0.01
<0.0001
Concomitant antiplatelet
• Aspirin
• Clopidogrel
36
4.5
36
4.2
38
6.98
0.4
0.01
ORBIT-AF
Adapted from: Steinberg et al. Circulation. 2014.
ORBIT-AF
• Categorical variables
– Frequencies/percentages
– Differences between 2 groups: Chi-square test
• Continuous variables
– Mean/median
– Differences between 2 groups: Wilcoxon rank sum test
Steinberg et al. Circulation. 2014.
ORBIT-AF: Results
Adjusted 30-day outcomes, by use of bridging anticoagulation
Unadjusted, % (n) Adjusted
No bridging
(N=1724)
Bridging
(N=503)
P-value Adjusted OR (95%
CI), bridging vs no
bridging
P-value
Cardiovascular events 2.5 (43) 4.3 (23) 0.02 1.62 (0.95-2.78) 0.07
Bleeding events 1.3 (22) 5.0 (25) <0.0001 3.84 (2.07-7.14) <0.0001
Overall composite* 6.3 (108) 13 (64) <0.0001 1.94 (1.38-2.71) 0.0001
*Composite of any MI, stroke, systemic embolism, or death within
30 days following date of procedure requiring interruption Adapted from: Steinberg et al. Circulation. 2014.
ORBIT-AF
Limitations
Observational study design
Why was decision made to interrupt OAC in some cases
and not others?
Therapeutic vs. prophylactic dosing?
Reversal agents used?
No data on the timing of initiation and discontinuation of
bridging agents
ORBIT-AF
• Significance
– Results consistent with previous literature data on
safety and efficacy of bridging anticoagulation in AF
patients
– Large, real-world population of outpatients
– Room for improvement in types of procedures not
requiring interruption of warfarin therapy
Conclusion
• Results suggest bridging anticoagulation in atrial
fibrillation may be harmful
• Data show an increased risk of bleeding in patients
receiving bridging anticoagulation, and no difference in
thromboembolic events
• Additional data needed to identify best practices
Steinberg et al. Circulation. 2014.
Perioperative Bridging Anticoagulation in
Patients with Atrial Fibrillation (BRIDGE Trial)
Douketis J, Spyropoulos A, Kaatz S, et al. NEJM. 2015.
BRIDGE
• Study Question
– Is bridging anticoagulation necessary during
perioperative warfarin interruption for patients
with atrial fibrillation or atrial flutter?
Douketis et al. N Engl J Med. 2015.
BRIDGE
• Methods
– Randomized, double blind, placebo controlled
• 108 sites
• July 2009 through December 2014
– Bridging anticoagulation vs. placebo
• Warfarin stopped 5 days prior to procedure, and resumed within
24 hours after procedure
• 100 IU dalteparin/kg or matching placebo SC BID from 3 days
before procedure then 5-10 days after
Douketis et al. N Engl J Med. 2015.
BRIDGE Inclusion • ≥18 years old
• Chronic atrial fibrillation or atrial flutter
• Warfarin use ≥3 months
• INR 2-3
• Elective operation or invasive procedure
• At least 1 CHADS2 risk factor
Exclusion • Mechanical heart valve
• Stroke, systemic embolism or TIA within previous 12 weeks
• Major bleeding within previous 6 weeks
• CrCl <30 ml/min
• Platelet count <100,000/mm3
• Planned cardiac, intracranial, or intraspinal surgery
Douketis et al. N Engl J Med. 2015.
BRIDGE
• Study Outcomes
– Primary
• Arterial thromboembolism
– Stroke, TIA, systemic embolism
• Major bleeding
– Secondary
• Acute MI, DVT, PE and death
• Minor bleeding
Douketis et al. N Engl J Med. 2015.
BRIDGE
• Statistical Analysis
– Assumptions
• Rate of arterial thromboembolism in bridging group: 1%
• Rate of arterial thromboembolism in placebo group: 1%
– Statistical tests
• Arterial thromboembolism
– Noninferiority analysis: one sided at 0.025 significance level
» Barnard’s test: used to calculate 95% confidence interval for difference in event
rate
• Bleeding
– Two sided test at 0.05 significance level
– Fisher’s mid-P test to calculate p-values
– 90% powered to detect primary endpoints
Douketis et al. N Engl J Med. 2015.
1,884Randomized
950Placebo
934Dalteparin
32 Discontinued study
• 23 withdrew
consent
• 3 lost to follow up
• 2 withdrawn by
principal
investigator
• 4 other reasons
5 died
Results
6,585Patient’s screened
913Completed Study
891Completed study
39 Discontinued study
• 31 withdrew
consent
• 3 lost to follow up
• 1 withdrawn by
principal
investigator
• 4 other reasons
4 died
Douketis et al. N Engl J Med. 2015.
BRIDGE
Baseline Characteristics
No Bridging
(N = 950)
Bridging
(N = 934)
Age, yr 71.8 71.6
Male sex – no. (%) 696 (73.3) 686 (73.4)
CHF or LV dysfunction – no. (%) 289 (30.4) 310 (33.2)
Hypertension – no. (%) 833 (87.7) 806 (86.3)
Diabetes mellitus – no. (%) 390 (41.1) 382 (40.9)
Stroke – no. (%) 79 (8.3) 99 (10.6)
TIA – no. (%) 79 (8.0) 77 (8.2)
Douketis et al. N Engl J Med. 2015.
BRIDGEBaseline Characteristics
CHADS2 score No Bridging
(N = 950)
Bridging
(N = 934)
• Mean
• Distribution – no. (%)
0
1
2
3
4
5
6
2.3
1 (0.1)
216 (22.7)
382 (40.2)
229 (24.1)
96 (10.1)
23 (2.4)
3 (0.3)
2.4
1 (0.1)
212 (22.7)
351 (37.6)
232 (24.8)
106 (11.3)
27 (2.9)
5 (0.5)
Douketis et al. N Engl J Med. 2015.
BRIDGEBaseline Characteristics
No Bridging
(N = 950)
Bridging
(N = 934)
Medication use – no. (%)
• Aspirin
• Clopidogrel
• NSAIDs
• COX-2 inhibitor
324 (34.1)
30 (3.2)
34 (3.6)
8 (0.8)
329 (35.2)
21 (2.2)
25 (2.7)
13 (1.4)
Douketis et al. N Engl J Med. 2015.
BRIDGE - Results
Results – Primary Outcomes
No Bridging
(N = 918)
Bridging
(N = 895)
P Value
Arterial thromboembolism
• Stroke
• TIA
• Systemic embolism
4 (0.4)
2 (0.2)
2 (0.2)
0
3 (0.3)
3 (0.3)
0
0
0.01a, 0.73b
Major Bleeding 12 (1.3) 29 (3.2) 0.005b
a: p value for noninferiority
b: p value for superiority Douketis et al. N Engl J Med. 2015.
BRIDGE - Results
Results – Secondary Outcomes
No Bridging
(N = 918)
Bridging
(N = 895)
P Value
Death 5 (0.5) 4 (0.4) 0.88b
MI 7 (0.8) 14 (1.6) 0.1b
DVT 0 1 (0.1) 0.25b
PE 0 1 (0.1) 0.25b
Minor bleeding 110 (12) 187 (20.9) <0.001b
a: p value for noninferiority
b: p value for superiority Douketis et al. N Engl J Med. 2015.
BRIDGE
Limitations
Average CHADSs score of 2.3
Major surgeries not addressed
Overall rate of thromboembolism lower than expected
Observed rate of bleeding modest
Diminished relevance?
BRIDGE - Conclusions
• Discontinuation of warfarin therapy without the use of bridging
anticoagulation was noninferior to the use of bridging
anticoagulation for the prevention of arterial thromboembolism.
• Bridging conferred a risk of major bleeding that was nearly triple the
risk associated with no bridging.
• Results are consistent with those from nonrandomized comparisons
of these strategies.
A Double Blind Randomized Control Trial of Post-Operative Low
Molecular Weight Heparin Bridging Therapy Versus Placebo
Bridging Therapy for Patients Who Are at High Risk for Arterial
Thromboembolism
PERIOP-2
Kovacs MJ. ClinicalTrials.gov. 2014.
PERIOP-2
PERIOP-2
Study design • Phase III
• Prospective
• Randomized
• Placebo controlled
• Double blind
Intervention • Bridging vs. no bridging in
surgeries or procedures
requiring warfarin interruption
Primary outcome • Major thromboembolism
Patients • Mechanical heart valve
• Atrial fibrillation
Results • Expected March 2015
Kovacs MJ. ClinicalTrials.gov. 2014.
What About NOAC?
• Rapid onset of action
– Consider use of LMWH or UFH in patients unable to restart oral NOAC following surgery
• No evidence to suggest use of these agents for bridging to warfarin
– Apixaban: May interact with INR. Discontinue apixaban and start a parenteral therapy if
anticoagulation until INR is therapeutic is needed
Rivaroxaban
(Xarelto®)
Apixaban
(Eliquis®)
Dabigatran
(Pradaxa®)
Time to
Onset
2 - 4 hours 3 - 4 hours 1 - 2 hours
Half Life 5 - 9 hours 12 hours 15 hours
Conclusion
• MW is a 63 year old male s/p right kidney biopsy receiving OAC therapy
with warfarin for atrial fibrillation. Warfarin was held 4 days prior to
procedure. PMH is significant for type 2 diabetes mellitus, coronary artery
disease, and hypertension. No previous stroke or TIA. INR upon arrival
back to the medical unit is 1.1.
• CHADS2 score = 2 (low risk thromboembolism)
• The MD orders enoxaparin 1mg/kg BID to start tomorrow AM, and warfarin
to re-start this evening. What do you do?
– Verify the enoxaparin order of 1mg/kg BID
– Call the MD to suggest bridging with UFH instead of enoxaparin.
– Call the MD to suggest not bridging in this patient
– Call the MD to suggest prophylaxis enoxaparin dosing (40mg daily)
Conclusion
• Guidelines on the use of bridging OAC are based largely on
observational data, and lack specific recommendations.
• The ORBIT-AF and BRIDGE trials conclude that patients
receiving bridging anticoagulation are at a higher risk of bleeding
than those that did not receive bridging anticoagulation.
• In patients with atrial fibrillation without a MHV considered low
risk or moderate risk for thromboembolism, bridging
anticoagulation should not be used.
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Cardiol 2014; 64:e1-76.
• Kovacs MJ. PERIOP-2: A safety and effectiveness study of LMWH bridging therapy versus placebo bridging therapy for patients on long
term warfarin and require temporary interruption of their warfarin. www.ClinicalTrials.gov. Identifier: NCT00432796. Accessed February
28, 2015
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Recommended